Leptin regulation of Hsp60 impacts hypothalamic insulin signaling
André Kleinridders, … , Peter Bross, C. Ronald Kahn
André Kleinridders, … , Peter Bross, C. Ronald Kahn
Published October 1, 2013
Citation Information: J Clin Invest. 2013;123(11):4667-4680. https://doi.org/10.1172/JCI67615.
View: Text | PDF
Research Article Metabolism

Leptin regulation of Hsp60 impacts hypothalamic insulin signaling

Abstract

Type 2 diabetes is characterized by insulin resistance and mitochondrial dysfunction in classical target tissues such as muscle, fat, and liver. Using a murine model of type 2 diabetes, we show that there is hypothalamic insulin resistance and mitochondrial dysfunction due to downregulation of the mitochondrial chaperone HSP60. HSP60 reduction in obese, diabetic mice was due to a lack of proper leptin signaling and was restored by leptin treatment. Knockdown of Hsp60 in a mouse hypothalamic cell line mimicked the mitochondrial dysfunction observed in diabetic mice and resulted in increased ROS production and insulin resistance, a phenotype that was reversed with antioxidant treatment. Mice with a heterozygous deletion of Hsp60 exhibited mitochondrial dysfunction and hypothalamic insulin resistance. Targeted acute downregulation of Hsp60 in the hypothalamus also induced insulin resistance, indicating that mitochondrial dysfunction can cause insulin resistance in the hypothalamus. Importantly, type 2 diabetic patients exhibited decreased expression of HSP60 in the brain, indicating that this mechanism is relevant to human disease. These data indicate that leptin plays an important role in mitochondrial function and insulin sensitivity in the hypothalamus by regulating HSP60. Moreover, leptin/insulin crosstalk in the hypothalamus impacts energy homeostasis in obesity and insulin-resistant states.

Authors

André Kleinridders, Hans P.M.M. Lauritzen, Siegfried Ussar, Jane H. Christensen, Marcelo A. Mori, Peter Bross, C. Ronald Kahn

×

Figure 6

Acute HSP60 deficiency in the hypothalamus causes insulin resistance.

Options: View larger image (or click on image) Download as PowerPoint
Acute HSP60 deficiency in the hypothalamus causes insulin resistance. (A...
(A) Gene expression and (B) Western blot and densitometric analysis of HSP60 in hypothalami of control and HSP60 KD mice (n = 7–8). (C) Randomly fed blood glucose levels of control and HSP60 KD mice (n = 7–8). (D) Average daily food intake of control and HSP60 KD mice (n = 7–8). (E) Gene expression analysis of orexigenic and anorexigenic neuropeptides of control and HSP60 KD mice (n = 7–8). (F) Western blot and (G) densitometric analysis of phosphorylated IRS1 Ser307 and JNK (n = 7–8). (H) Gene expression analysis of inflammatory markers and SOCS3 in control and HSP60 KD mice (n = 7–8). Displayed values are the means ± SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.